The long-term objective of this project is to breed selectively for the propensity to orally self-administer opiates. Beginning with the N:NIH heterogeneous rat stock, animals will be identified which preferentially seek or avoid the high-potency opiate etonitazene, in a situation in which it is presented continuously as a choice with water. Over generations, preferences will be measured and selection pressure imposed in order to establish reproductively independent, duplicate lines of pressure imposed in order to establish reproductively independent, duplicate lines of high- preference (HP), low-preference (LP), and randomly-bred control rats. During significant divergence of the lines, relevant differences among them will be investigated. Using standard behavioral and biochemical assays, specific aims are to answer the following questions. 1) Is the basis of differences pharmacokinetic, i.e., do they metabolize opiates differently? 2) Will concurrent administration of an opiate antagonist cause preference to be lost, byu blocking the post-ingestive, presumably CNS, effects of the etonitazene? 3) Does etonitazene serve as a reinforcer for HP but not for LP rats? 4) Are preferences specific to etonitazene, or do HP and LP rats exhibit the same behaviors toward other chemically unrelated drugs such as ethanol? 5) Do the lines differ in sensitivity to the analgesic effects of opiates? 6) Will HP rats freely drink enough etonitazene to become physically dependent? 7) Are there differences between the lines in receptor binding profiles, especially in brain areas associated with reward? 8) Are the major neurotransmitter systems altered by selection, particularly in brain regions involved in opiate actions? 9) Is the composition of gangliosides in these brain regions affected by selective breeding? By bringing the propensity to voluntarily ingest opiates under genetic control, one can address questions which are fundamental to an analysis of drug self-administration behavior. The long-range goal is that information about these animals' behavior and neurochemistry will contribute to our understanding of why only some people self-administer opiates.